MDM2 is a novel E3 ligase for HIV-1 Vif

The human immunodeficiency virus type 1 (HIV-1) Vif plays a crucial role in the viral life cycle by antagonizing a host restriction factor APOBEC3G (A3G). Vif interacts with A3G and induces its polyubiquitination and subsequent degradation via the formation of active ubiquitin ligase (E3) complex with Cullin5-ElonginB/C. Although Vif itself is also ubiquitinated and degraded rapidly in infected cells, precise roles and mechanisms of Vif ubiquitination are largely unknown. Here we report that MDM2, known as an E3 ligase for p53, is a novel E3 ligase for Vif and induces polyubiquitination and degradation of Vif. We also show the mechanisms by which MDM2 only targets Vif, but not A3G that binds to Vif. MDM2 reduces cellular Vif levels and reversely increases A3G levels, because the interaction between MDM2 and Vif precludes A3G from binding to Vif. Furthermore, we demonstrate that MDM2 negatively regulates HIV-1 replication in non-permissive target cells through Vif degradation. These data suggest that MDM2 is a regulator of HIV-1 replication and might be a novel therapeutic target for anti-HIV-1 drug

Loss of runt-related transcription factor 3 expression leads hepatocellular carcinoma cells to escape apoptosis

Background: Runt-related transcription factor 3 (RUNX3) is known as a tumor suppressor gene for gastric cancer and other cancers, this gene may be involved in the development of hepatocellular carcinoma (HCC). Methods: RUNX3 expression was analyzed by immunoblot and immunohistochemistry in HCC cells and tissues, respectively. Hep3B cells, lacking endogenous RUNX3, were introduced with RUNX3 constructs. Cell proliferation was measured using the MTT assay and apoptosis was evaluated using DAPI staining. Apoptosis signaling was assessed by immunoblot analysis. Results: RUNX3 protein expression was frequently inactivated in the HCC cell lines (91%) and tissues (90%). RUNX3 expression inhibited 90 +/- 8% of cell growth at 72 h in serum starved Hep3B cells. Forty-eight hour serum starvation-induced apoptosis and the percentage of apoptotic cells reached 31 +/- 4% and 4 +/- 1% in RUNX3-expressing Hep3B and control cells, respectively. Apoptotic activity was increased by Bim expression and caspase-3 and caspase-9 activation. Conclusion: RUNX3 expression enhanced serum starvation-induced apoptosis in HCC cell lines. RUNX3 is deleted or weakly expressed in HCC, which leads to tumorigenesis by escaping apoptosis

Relationship among Left Ventricular Hypertrophy, Cardiovascular Events, and Preferred Blood Pressure Measurement Timing in Hemodialysis Patients

This study aimed to identify the ideal timing and setting for measuring blood pressure (BP) and determine whether the left ventricular mass index (LVMI) is an independent risk factor associated with increased cardiovascular events in hemodialysis (HD) patients. BP and LVMI were measured at baseline and at 6 and 12 months after HD initiation. BP was monitored and recorded at nine different time points, including before and after HD over a one-week period (HDBP). The mean BP measurement was calculated as the weekly averaged BP (WABP). LVMI was significantly correlated with home BP, in-office BP, HDBP, and WABP. Receiver operating characteristic analysis indicated that the cutoff LVMI value for cardiovascular events was 156 g/m2. LVMI and diabetes mellitus were significant influencing factors for cardiovascular events (hazards ratio (95% confidence interval): diabetes mellitus, 2.84 (1.17,7.45); LVMI > 156 g/m2, 2.86 (1.22,6.99)). Pre-HDBP, post-HDBP, and WABP were independently associated with higher LVMI in the follow-up periods. Hemoglobin and human atrial natriuretic peptide (hANP) levels were associated with LVMI beyond 12 months after HD initiation. Treatment of hypertension, overhydration based on hANP, and anemia may reduce the progression of LVMI and help identify HD patients at high risk for cardiovascular events

Partially Ordered Preferences in Decision Trees: Computing Strategies with Imprecision in Probabilities

info:eu-repo/semantics/publishe

Effects of l-Carnitine Supplementation in Patients Receiving Hemodialysis or Peritoneal Dialysis

l-carnitine is an important factor in fatty acid metabolism, and carnitine deficiency is common in dialysis patients. This study evaluated whether l-carnitine supplementation improved muscle spasm, cardiac function, and renal anemia in dialysis patients. Eighty Japanese outpatients (62 hemodialysis (HD) patients and 18 peritoneal dialysis (PD) patients) received oral l-carnitine (600 mg/day) for 12 months; the HD patients further received intravenous l-carnitine injections (1000 mg three times/week) for 12 months, amounting to 24 months of treatment. Muscle spasm incidence was assessed using a questionnaire, and cardiac function was assessed using echocardiography. Baseline free carnitine concentrations were relatively low in patients who underwent dialysis for >4 years. Total carnitine serum concentration, free carnitine, and acylcarnitine significantly increased after oral l-carnitine treatment for 12 months, and after intravenous l-carnitine injection. There was no significant improvement in muscle spasms, although decreased muscle cramping after l-carnitine treatment was reported by 31% of patients who had undergone HD for >4 years. Hemoglobin concentrations increased significantly at 12 and 24 months in the HD group. Therefore, l-carnitine may be effective for reducing muscle cramping and improving hemoglobin levels in dialysis patients, especially those who have been undergoing dialysis for >4 years

Impact of Transferrin Saturation and Anemia on Radial Artery Calcification in Patients with End-Stage Kidney Disease

Background: Arterial calcification is an important factor in determining the prognosis of patients with chronic kidney disease (CKD). Few studies on aortic calcification have involved radial artery calcification (RAC). This study aimed to analyze risk factors for RAC in patients with end-stage kidney disease (ESKD) and investigate the relationship between subsequent cardiovascular events (CVE) and vascular access trouble (VAT). Methods: This cohort study included 64 consecutive patients with ESKD who initiated hemodialysis and underwent a procedure for the creation of a primary radiocephalic arteriovenous fistula (RCAVF). Small arterial specimens were obtained from patients during RCAVF surgery. Tissue samples were stained with von Kossa, and arterial microcalcification was evaluated. We analyzed the association between preexisting arterial microcalcifications, clinical characteristics, CVE, and VAT. Results: In the univariate analysis, RAC patients demonstrated high systolic blood pressure (sBP), low hemoglobin (Hb), and low transferrin saturation (TSAT) (<0.05, <0.05, and <0.05, respectively). In the multivariate analysis, Hb (HR–0.516 (0.278–0.959), p < 0.05), TSAT (HR–0.0012 (0.00000248–0.597), p < 0.05), and sBP (HR–1.037 (1.001–1.073), p < 0.05) were independent risk factors for RAC. The cumulative incidence rate of CVE/VAT was not associated with RAC for one year. Conclusion: RAC was associated with sBP, TSAT, and anemia; however, no association with CVE/VAT was observed